Schizophrenia is a common, debilitating, sometimes life-threatening illness. In the 1990 World Health Organization ranking of public health burden in developed regions (Murray and Lopez, 1996), schizophrenia lay ahead of diabetes, cirrhosis, drug use, breast cancer, asthma, rheumatoid arthritis, and HIV. Currently available treatments for schizophrenia include both conventional antipsychotics, which were first developed in the late 1950s, as well as new generation atypical antipsychotics, which have been developed over the past decade. Despite recent advances in treatment including the new generation medications, most schizophrenic patients continue to remain chronically disabled. Because the disorder typically arises in adolescents and young adults, the resulting chronicity too often is life long.
Schizophrenia Prodrome—Need for New Treatments
Although schizophrenia is heterogenous, most patients may be characterized as following a course consisting of premorbid, prodromal, and psychotic illness phases (Woods and McGlashan, 2005). The premorbid phase describes an asymptomatic period of normality or relatively subtle and stable impairments starting from birth. The prodromal phase is conceptualized as the first symptomatic phase, and is shorter in duration and escalating in severity. When patients become fully psychotic they are defined as having experienced the onset of schizophrenia as we currently conceptualize it. Current treatment guidelines apply only to the frankly psychotic phase of illness post onset.
The prodromal phase of schizophrenic disorders has been recognized since the 19th century (Bleuler, 1911). The possibility of treatment intervention during the prodromal phase has a history almost as long (Sullivan, 1927). A recent strong resurgent interest in this area (McGlashan, 1998; McGlashan and Johannessen, 1996; McGorry, 1998; Stephenson, 1999) stems largely from two developments.
First, neurobiological deficit processes associated with the severity and chronicity of schizophrenia have been demonstrated already to be present by the time onset is recognized (McGlashan and Johannessen, 1996). Thus these deficit processes begin before onset of illness as we currently define it. Intervention during the prodrome offers hope of influencing these processes earlier in their development.
Second, most (see (Lieberman et al., 2001; Norman and Malla, 2001; Woods et al., 2001) for reviews) although not all (Barnes et al., 2000; Chen et al., 1999; Craig et al., 2000; Ho et al., 2000; Robinson et al., 1999)) studies with antipsychotic medication suggest that treatment earlier in the active phase may be associated with better long term outcome than delayed application of the same treatment. Max Marshall (Marshall et al., 2003) and Jeff Lieberman (personal communication) have each conducted formal meta-analyses to this literature, each of which reveal a strong positive overall effect of earlier treatment. These results suggest that intervention earlier in the course of illness, before the active phase, may be associated with even better long-term outcome. Prevention of the chronic disability of schizophrenia could even be envisioned.
Substantial progress has been made in recent years in addressing the accuracy of patient identification during the prodromal phase. Our group has elaborated criteria and a structured interview for diagnosing the prodromal phase (the Structured Interview for Prodromal Syndromes (SIPS) (Woods et al., 2001)). The criteria are based on subthreshold levels of positive symptoms of schizophrenia such as attenuated delusions (unusual thought content) and attenuated hallucinations (perceptual abnormalities). We have shown that reliability of the prodromal diagnosis is excellent (Miller et al., 2002; Miller et al., 2003a) and that prodromal patients are highly symptomatic (Miller et al., 2003b; Woods et al., 2001), functionally impaired (McGlashan et al., 2001; Miller et al., 2003b), cognitively impaired (Hawkins et al., 2004a), and treatment-seeking (Preda et al., 2002). In addition, these patients are at risk for schizophrenia. Onset risk in 12 months was 54% in our without treatment sample (Miller et al., 2002) and 47% in second sample randomized to placebo (Miller et al., 2004). Onset risk has been similar, about 30-50% in the next year, in other sites around the world that use similar criteria (Morrison et al., 2004; Yung et al., 2003). Taken together, we believe this evidence indicates that these patients constitute a new clinical population in need of effective treatment and definition of a standard of care.
Only three studies thus far have addressed treatment needs of prodromal patients. The first two studied antipsychotic medication. A recently completed trial randomized 59 patients to open-label risperidone plus cognitive therapy plus usual care versus usual care alone (McGorry et al., 2002). Six month conversion to psychosis rates were 9.7% for the risperidone containing treatment and 35.7% for usual care (p<0.05). Our group has completed a 12 month trial randomizing 60 patients to olanzapine vs placebo (McGlashan et al., 2004; Woods et al., 2003). Twelve month conversion rates were 16% for olanzapine and 38% for placebo, a statistically significant difference when controlling for baseline severity imbalance. The third study randomized 58 prodromal patients to cognitive therapy vs monitoring (Morrison et al., 2004). Cognitive therapy group showed significantly lower rates when two patients later believed to have been already psychotic were excluded.
Prodromal research studies thus far have focused primarily on the aim of preventing the development of schizophrenic psychosis. While this is certainly an important goal, ethical issues are raised because some patients will be false positives who have no personal opportunity to benefit if benefit is defined solely as prevention. Prodromal patients are highly symptomatic, yet little attention has thus far been paid to determining whether treatment improves the patients' current symptoms. Focusing on symptomatic improvement lessens ethical concerns because each patient enrolled will personally have prospect of benefit to balance off against risk (Woods et al., 2001). Our group conducted such analyses over the short term in its olanzapine vs placebo trial, using the SOPS as the primary outcome measure (Woods et at., 2003). The results showed that prodromal symptoms improved significantly more with placebo than with olanzapine. Prodromal patients changed little with placebo.
NMDA Hypofunction—A Novel Neurobiologic Target for Treatment in the Schizophrenia Prodrome
Antipsychotic medications were tried first for prodromal patients. A part of the concern about prodromal intervention is that even the new atypical antipsychotics can have worrisome side effects, including weight gain and metabolic syndrome. Many of these side effects can be more prominent in adolescents than in adults (Woods et al., 2002). Although it makes sense that antipsychotic medications would be tried first for prodromal patients, the prodrome may involve neurotoxic or degenerative processes that are distinct from the neurobiology associated with the chronic stages of schizophrenia. Other medications, perhaps only weakly effective for chronic patients, could influence the potentially unique neurobiology of the prodromal phase and might thereby improve prodromal symptoms and/or prevent schizophrenia from developing.
There are numerous examples throughout medicine where the same treatment can be fully effective and even curative when given early in the course of illness and yet less effective or even completely ineffective later in the course of illness after the pathophysiology has changed. One familiar example is neonatal hypothyroidism (cretinism). This condition is asymptomatic at birth because the fetus has developed normally due to access to maternal thyroid hormone. If the illness is detected by screening shortly after birth, early thyroid hormone supplementation allows fully normal postnatal neurologic development. However, if the illness is not detected until neurologic symptoms develop, later thyroid hormone supplementation corrects thyroid hormone levels but does not restore normal neurologic functioning, and the child remains chronically developmentally disabled.
All currently approved treatments for schizophrenia, including both typical and atypical antipsychotics, were developed based upon dopaminergic theories of schizophrenia and function primarily by blocking neurotransmission at D2-type dopamine receptors, with interactions at other receptors producing only a portion of the variability in clinical effectiveness between agents (Kapur and Remington, 2001). These were also the first agents to be tested for the schizophrenia prodrome (McGorry et al., 2002; Woods et al., 2003). The novel treatment proposed for the schizophrenia prodrome in this patent application is based upon an alternative, glutamatergic or NMDA hypofunction model of schizophrenia and its prodrome (see below).